The long-term objectives are to describe the effects of bile acids and fatty acids on the intestinal tract, to define the mechanisms by which they alter intestinal function and to describe the mechanisms by which the intestine is normally protected from their adverse effects. The specific aims of this proposal are: 1) To study the effects of bile acids and fatty acids on confluent monolayers of T84 cells grown in tissue culture, a simple model for an epithelium of intestinal origin, capable of secretion. These investigations include: a) study of their effects on short circuit current, potential difference, tissue conductance and unidirectional electrolyte fluxes in Ussing chambers; b) studies of the effects on the permeability of tight junctions; c) studies of the effects on the passive permeability of the apical and basolateral membranes for electrolytes and on membrane injury d) studies on the effects on c-AMP content; e) study of structure activity relationships for bile acids in this model with respect to effects on electrical parameters of the Ussing chamber, membrane injury and binding of bile acids to the apical or basolateral membrane; f) localization of bile acids on the surface and within T84 cells by autoradiography-electronmicroscopy, g) studies of the mechanisms by which phospholipids and cholesterol protect against the effects of bile acids and fatty acids in the system. 2) To determine whether bile acids reach intestinal crypts during in vivo perfusion experiments. 3) To describe the passage of bile acids across enterocytes in the jejunum and ileum. These studies will further our understanding of the mechanisms by which bile acids and fatty acids, normally present in the intestine, affect intestinal function and how they cause diarrhea in certain disease states.